Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Functional and Structural Relevance of Conserved Positively Charged Lysine Residues in Organic Anion Transporting Polypeptide 1B3

Kathrin Mandery, Heinrich Sticht, Krystyna Bujok, Ingrid Schmidt, Christina Fahrmayr, Bettina Balk, Martin F. Fromm and Hartmut Glaeser
Molecular Pharmacology September 2011, 80 (3) 400-406; DOI: https://doi.org/10.1124/mol.111.071282
Kathrin Mandery
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heinrich Sticht
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Krystyna Bujok
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ingrid Schmidt
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christina Fahrmayr
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bettina Balk
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin F. Fromm
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hartmut Glaeser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

The human organic anion transporting polypeptide 1B3 (OATP1B3), located in the basolateral membrane of hepatocytes, mediates the uptake of endogenous substrates such as taurocholate and drugs from blood into hepatocytes. The transport activity of OATP1B3 is influenced by positively charged amino acids, which are facing the central pore. Molecular modeling was performed to select conserved positively charged amino acids, which may influence transport activity and anchoring of OATP1B3 in the plasma membrane. The modeling revealed that Lys361 faces the pore, and Lys399 is oriented to the plasma membrane. Therefore, the mutants L361>A, L361>R, L399>A, and L399>R were generated using site-directed mutagenesis to investigate the impact of the positive charges on transport activity and anchoring in the membrane. Transport kinetic analyses for the substrates sulfobromophthalein and taurocholate showed a loss of function for the L361>A mutant, whereas the transport activity was maintained by the L361>R mutant, indicating that the positive charge at position 361 is important for transport activity of OATP1B3. Comparative modeling with OATP1A2 and OATP2B1 revealed that the pore size around this lysine residue is larger in OATP1A2 and smaller in OATP2B1 compared with OATP1B3, which could be related to the respective substrate spectra. Cell surface expression of L399>A and L399>R was decreased to 16 and 72% compared with wild-type OATP1B3 (p < 0.001), respectively, indicating that the positive charge of lysine at position 399 is necessary for an unimpaired cell surface expression. Furthermore, we provide a summary of amino acids, which influence the transport activity of OATP1B3.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft [Grants DFG GL588/2-1, DFG GL588/3-1, DFG FR1298/5-1].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071282.

  • ABBREVIATIONS:

    OATP/Oatp
    organic anion transporting polypeptide
    BSP
    sulfobromophthalein
    PGE2
    prostaglandin E2
    E3S
    estron-3-sulfate
    E17βG
    estradiol-17β-glucuronide
    CCK-8
    cholecystokinin 8
    ANOVA
    analysis of variance
    WT
    wild type.

  • Received January 17, 2011.
  • Accepted June 3, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Functional and Structural Relevance of Conserved Positively Charged Lysine Residues in Organic Anion Transporting Polypeptide 1B3
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Functional and Structural Relevance of Conserved Positively Charged Lysine Residues in Organic Anion Transporting Polypeptide 1B3

Kathrin Mandery, Heinrich Sticht, Krystyna Bujok, Ingrid Schmidt, Christina Fahrmayr, Bettina Balk, Martin F. Fromm and Hartmut Glaeser
Molecular Pharmacology September 1, 2011, 80 (3) 400-406; DOI: https://doi.org/10.1124/mol.111.071282

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Functional and Structural Relevance of Conserved Positively Charged Lysine Residues in Organic Anion Transporting Polypeptide 1B3

Kathrin Mandery, Heinrich Sticht, Krystyna Bujok, Ingrid Schmidt, Christina Fahrmayr, Bettina Balk, Martin F. Fromm and Hartmut Glaeser
Molecular Pharmacology September 1, 2011, 80 (3) 400-406; DOI: https://doi.org/10.1124/mol.111.071282
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
  • Benzbromarone relaxes airway smooth muscle via BK activation
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics